CA2013519C

CA2013519C - Sulfonyl derivatives of thieno-triazolo-diazepines, a preparation process of the same and therapeutic compositions containing them

Info

Publication number: CA2013519C
Application number: CA002013519A
Authority: CA
Inventors: Andre Esanu; Jean-Pierre Laurent; Christiane Martin; Pierre Braquet
Original assignee: Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
Current assignee: Ipsen Pharma SAS
Priority date: 1989-03-31
Filing date: 1990-03-30
Publication date: 2004-02-24
Anticipated expiration: 2010-03-30
Also published as: NL9000625A; SE9000872L; FR2645023B1; US5049560A; GB9007075D0; GB8907257D0; CH680589A5; ES2019244A6; IE900805L; IT9019883A0; SG90392G; MY105589A; GR1000420B; FR2645154B1; MA21791A1; FR2645023A1; TNSN90043A1; GB2229724A; FI95037C; DE4010361A1

Abstract

This invention relates to thieno-triazolo-diazepine derivatives of the formula wherein R represents various substituents to a preparation process of these compounds consisting in reacting the thieno-triazolo-diazepine compound of the formula

Description

~~~.3~9L.~
The present invention relates to new sulfonyl derivatives of thieno-triazolo-diazepine which are particularly interesting as anti-PAF arid anti-ischemic agents.
The invention more particularly relates to thieno-triazolo-diazepine derivatives of the formula I:
R~SOZ~1 I
wherein R represents:
- a straight chain or branched chain alkyl group having from 1 to 20 carbon atoms;
- a phenyl group, unsubstituted or substituted by an l0 halogen atom, a straight chain or branched chain alkyl group having from 1 to 8 carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, a carboxy group or an alkylsulfonyl group or an alkylthio group, or a trifluoromethyl group or an optionally substituted phenoxy group or - a furyl, thienyl, pyrrolyl, quinalyl, naphtyl group and therapeutically acceptable salts thereof.

~~.1'~~~~.~
This invention relates also to a preparation process of said compounds consisting in reacting the thieno-triazolo-diazepine compound of the formula II:

N
II
H~1 CHa ' 'N
'N/
on RS02C1 in the presence of a mild basic agent, in a polar solvent, at a temperature between, preferably, 10° and 30'C.
The prior art in the field of this invention, may be illustrated by US patent 4 621 083 (or E.P. 176 927) in which thieno-triazolo-diazepine having PAF-antagonistic activity are disclosed.
This invention relates, finally, to therapeutic compositions containing these compounds.
These new compounds present a PAF-antagonistic activity from ten to thousand times greater than this one of the diazepines disclosed in the above mentionned patent, and also a more potent effectiveness.
The preparation of the starting material is described in the following preparative examples from I to X.
I - (2-chloro)benzovlmethvl cyanide:

C -CHZ ~CN
O

In an appropriate reactor placed under nitrogen circulation at - 70°C were poured 7 1 of anhydrous THF and 115.9 g (1.36 mol) of previously dried cyanoacetic acid. Then were thus added dropwise 1 7I5 ml (2.74 mol) of 1,6 M solution of butyllithium in hexane, while allowing temperature to rise from - 70°C to 0°C. The reactional mixture was then stirred for one hour. Thereafter the reactional mixture was once more cooled at - 70°C and a solution of 120 g (0.685 mol) of chloro-2 benzoyle chloride in 1 1 of anhydrous THF, was added dropwise.
After stirring for one hour at always - 70°C, the temperature was allowed to rise from - 70°C to 0°G for one hour. Then there was added dropwise 3 1 of 1N HC1 solution and after stirring for a few minutes, the reacted mixture was extracted by chloroform. The organic phase was washed with a 10 % aqueous sodium bicarbonate solution, then with a saturated sodium chloride solution, dried, filtered and the solvent was evaporated off to give 135 g of residue.
The crystallization was effected by the addition of diisopropyl ether, and the product was filtered off, and washed with hexane to give 97.2 g of the title compound (Yield 79 %).
II - 2-amino - 3-(2-chlorobenzoLrl) - 6-(ethoxycarbonvl) 4, 5,6,7 tetrahydro- vrido 3,4 - b1 thin hens.

C. O
CzHs--O..C. N
g/ 'NHZ
O

~~~.:~J1.~

In a two litre-erlen fitted with a cooler, were poured 85.5 g (0.501 mol) of N-carbethoxy-4-piperidone, 90 g (0.501 mol) of (I), 19.3 g (0.600 mol) of flower of sulfur and 44.4 g (0.501 mol) of morpholine, in 550 ml of methanol. The mixture was refluxed for one hour. After evaporation of 250 ml of solvent, the desired compound precipitates, was filtered off, washed with ethanol, then with diethyl ether and dried to yield 155.4 g (85 %) of the title compound.
III - 2-(bromoacetamido) - 3-(2-chlorobenzoyl) - 6 (ethoxy carbonyl) - 4,5,6,7-tetrahvdro-pvrido (3,4 b1 thiophene.

Coo CzH50~C~ N
g NH~C~CHZ-Br O
In a five litre-reactor fitted with appropriate means and with separating funnel, were poured 2.5 1 of chloroform and 146 g (0.400 mol) of (II).
Then, 87.7 g (0.43 mol) of bromoacetylbromide contained in the separating funnel ware added dropwise. The reactional mixture was stirred for one hour at room temperature, then washed with 300 ml of icy-water, and the organic phase was dried with anhydrous magnesium sulphate and filtered. The chloroform was evaporated off and the residue was treated with ethanol. The resulting precipitate was filtered off, washed with ethanol, then with diethyl ether, and dried to yield 184.6 g (95 %) of the title compound.

IV - 2-(aminoacetamido) - 3(~-chlorobenzovl) - 6-(ether carbonyl) - 4,5,6,7-tetrahydro - ~vrido X3,4 - b1 thiophene:
r, C1 c=a CZH60~C~ N
a g~ NH ~ C ~ CHZ NHZ
a In a five litre-reactor fittedx with a gaz-injector were poured 174.8 g (0.36 mol) of (III) and 3 litres of THF. The suspension was cooled at 0'G and then gazeous ammonia previously dried over potassium hydroxide was added. The addition was conducted in 8 hours. (60 g of ammonia ware absorbed). The mixture was stirred overnight at 0°C, then 2 litres of THF was evaporated off under reduced pressure, and 750 ml of ethyl acetate were added. After decantation, the organic phase was washed once with 300 ml of a 10 %
sodium chloride solution, three times with 300 ml of water, and dried with anhydrous magnesium sulphate. After filtration, the solvent was partially evaporated off at rotavapor. The precipitate was allowed to stand overnight in refrigerator.
After filtration, the precipitate was washed with diethyl ether and dried to give 119 g of the title compound. The 2o remaining organic phase was concentrated and treated with a mixture of 1.5 1 of diethyl ether/THF (3/1 by volume) to give 14.6 g of the title compound (overall yield 88 %).

~~?Z:~ i~.:~
-- s -V - 5-(2-chlornphenyl) - 8-(ethoxycarbonyl) - 6,7 8 9 tetrahydro - 3H - xwrido f 4',~ 3' ~4, 51 thieno f 3 , 2 f 1 1,4 diazepine - 2 one.
CZH50 ~ ~ ~1 H
O
In a two litre-reactor fitted with stirring, cooling and warming means and placed under nitrogen circulation were poured 126.6 g (0.3 mol) (IV) and 800 ml of pyridine. The reaction mixture was refluxed for 18 hours:
After having checked that all the starting material had reacted, the pyridine was partially evaporated at a rotavapor under reduced pressure.
The obtained (dark brown) oil was dissolved with 1 litre of ethanol. After cooling in an ice-bath, there was obtained a precipitate which was filtered off, washed with ethanol and diisopropyloxide to yield 101:3 g (83.6 %) of the title compound.
VI - 5-(2-chlorophenvl) - 8-(ethoxvcarbonvl) 6,7,8 9 tetrahvdro-3H-twrido '4',3':4,51 thieno 3 2 f1 11_4-diazepine - 2 thione.
~l CZHgO ~C~1 O
H s _ 7 _ In a three litre-reactor fitted with appropriate means, were poured 93 g (0.230 mol) of V and 1,75 1 of pyridine.
After solubilization were added 56.3 g (0.25 mol) of phosphorus pentasulphur, and the reaction mixture was then stirred for three hours at 80-85°C. Thereafter, the pyridine was evaporated off and the obtained residue treated with icy-water. The mixture was then extracted by methylene chloride, dried with anhydrous magnesium sulphate, filtered, evaporated arid treated with l0 diethyl-ether. Then the resulting product was filtered off, and treated with 700 ml of acetonitrile. The suspension was heated at 60°C for 30 minutes and then allowed to cool.
After filtration, and washing with acetonitrile, then with diethyl-ether, the residue Was dried to yield 80.2 g (83 %) of the title compound.
VII - 5-(2-chloro henvl) - 8-(ethoxycarbonyl) 2 hydrazino 6,7,8,9 tetrahydro 3H-pyrido 4~,3~~4 51 ttiieno j3,2-f1 1,4-diazepine.
CzHs,~.O.-C.~l O
NH
~2 In a two litre-reactor fitted with appropriate means and with separating funnel, were poured 73.5 g (0.175 mol) of VI and 1 1 of methanol. Then 26.4 ml (0.525 mol) of hydrazine hydrate contained in the separating funnel, were added at room temperature and the mixture was stirred for two hours at always room temperature.

'~''~~.,3~~. at _8_ Thereafter 1/7 of methanol were evaporated off at 30°C and the residue was allowed to crystallize overnight in refrigerator. After filtration, washing with diethyl-ether and drying, there was obtained 65.1 g of the title compound (yield 89 %).
VIII - 5-(2-chlorophenyl)- 8-(ethoxycarbanyl)- 2-aceta~ido amino - 6,7,8,9-tetrahydro-3H-~yrido ~4~,3~°4,51 thieno ~3,Z-fl 1,4-diazepine.

CsH60-C~ 1 O _.
NH
O

In a two litre reactor fitted with cooling means and placed l0 under nitrogen circulation, were poured 58.5 g (0.140 mol) of VII and 1 1 of tetrahydrofuran. Then 11 g (0.140 mol) of acetyl chloride and 150 ml of tetrahydrofuran were added.
The addition was conducted in 30 minutes at 0°C. The solution became red after stirring for 45 minutes. The tetrahydrofuran was then evaporated off and the resulting residue treated with icy-water. Then 17.5 g of sodium bicarbonate were added and the mixture was extracted with 1 1 of methylene chloride. The organic phase was washed once with water and dried with anhydrous magnesium sulphate. After filtration, the solvent was evaporated off and the resulting residue treated with diethyl-ether, filtered and dried to yield 54.1 g (84 %) of the title compound.

~~~.3 a~.~

IX - 6-(2-chlorophenvl~ - 9-(ethoxYaarbony~ - 7,8,9,10 tetrahydro-1-methyl-4H-pvrido X4';3'~4,51 thieno [3,2-f] 1,2,4-triazolo 4,3-a1 1,4-diazepine.
CxH60~C ~ 1 0 \
~N
In a two litre-reactor fitted with appropriate means and placed under nitrogen circulation, were poured 750 ml of acetic acid and 46.9 g (0.102 mol) of VIII. The (red) solution was slowly warmed over one hour to reflux temperature and the reflux was thus maintained for 15 minutes. The (yellow) solution was then concentrated at . 10 rotavapor at a bath temperature not exceeding 35~C, and the acetic acid was extracted off with 700 ml of toluene. The residue was then treated with diethyl-ether, filtered, washed with diethyl-ether, and dried to yield 42.8 g (95 %) of the title compound.
X - 6-(2-chloro~henvll 7,8,9,10-tetrahvdro 1 methyl 48 pyrido r4',3'~4,51 thieno 3,2 f1 1,2,4 triazolo f4,3-a1 1.4-diazepine.
H~ l ~(~~.~ i~L~
- to -In a one litre-reactor fitted with appropriate means, were poured 500 ml of mixture of bromhydric acid/acetic acid (30 % bromhydric acid by volume). Then 35.8 g (0.081 mol) of IX were added portionwise at 5°C and the mixture was then stirred at room temperature for five days (CCM
analysis showed traces of starting material). Thereafter, 250 ml of acetic acid were evaporated off and the compound precipitated. Then 250 ml of diethyl-ether were added and the mixture was stirred for 30 minutes. The precipitate was filtered off, washed with diethyl-ether and poured into a one litre-flask in which 500 ml of icy-water were added.
The pH was ajusted at pH 9.5 with addition of a 40 %
aqueous sodium hydroxide solution. The reaction mass temperature was maintained below 20'C. After extraction with dichloromethane, the organic phase was dried with anhydrous magnesium sulphate, filtered and the dichloromethane was partially evaporated off. Then 120 ml of ethyl acetate were added with stirring. After precipitation, 160 ml of diethyl-ether was added and the mixture was allowed to crystallize overnight in refrigerator. After filtration and washing with diethyl-ether, there was obtained 28.1 g of the title compound (yield 93,6 %).
The invention will be better understood from the description of the following examples.

6-(2-chlorophenyl) - 9-hexadecylsulphonyl - 7,8,9,10-tetra-hydro-1-methyl 4H-pyrido [4',3':4,5] thieno [3,2-f]
1,2,4-triazolo [4,3-a] 1,4-diazepine R = CH3 - (CHz) is -Into a 4 litre reactor there were poured 25 g (67.6 mM) of 6-(2-chlorophenyl) - 7,8,9,10-tetrahydro-1-methyl 4H-pyrido [4 ',3 ':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a]
1,4-diazepine, 11.21 g (81 mM) of KzCO~, 23.36 g (81 mM) Of ~:CD~.~ i~.~

hexadecysulphonyl chloride) and 2 litres of a 10/1 (volume) acetone/H20 mixture.
The reacting mixture was stirred for 3 hours at room temperature. After having checked that all the starting material had reacted, the solvent was evaporated off in a rotary evaporator at a temperature not exceeding 30°C.
The resulting compound precipitated and was filtered, washed twice with water, dried under reduced pressure, and then dissolved in methylene dichloride and washed with water. After drying the organic phase aver MgS04, the solution was filtered once more, evaporated to dryness in a rotary evaporator at a temperature not exceeding 30°C, then taken up in 0.5 litres of pentane and stirred overnight.
The compound was separated by filtration, washed with pentane and dried under reduced pressure.
Yield 38 g (85%) of an orange powder melting at 80°C
(Tottoli) insoluble in water at room temperature but soluble in DMSO. The elemental analysis and the infrared and Mgt analyses showed a good correspondence with the formula C'4H,eCIN502S2 (molecular weight 658.37) and with the above structure.
The following compounds have been prepared as described in Example 1, but starting with the appropriate chlorosulphonyl derivative.

6-(2-chlorophenyl) - 9-phenylsulphonyl - 7,8,9,10-tetra-hydro-1-methyl 4H-pyrido [4 ',3 ':4,5] thieno [3,2-f]
1,2,4-triazolo [4,3-a] 1,4-diazepine H = phenyl-'~f~~_~ a~.,~~

6-(2-chlorophenyl) - 9-(2,4,6-trichloro)phenylsulphonyl -7,8,9,10-tetrahydro-1-methyl 4H-pyrido [4 ',3 ':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine R = (2,4,6-trichloro)phenyl-6-(2-chlorophenyl) - 9-(trifluromethyl)phenylsulphonyl -'7,8,9,10-tetrahydro-1-methyl 4H-pyrido [4 ',3 ':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine R = (4-trifluoromethyl)phenyl-6-(2-chlorophenyl) - 9-(4,5,6-trimethoxy)phenylsulphonyl -~.8.9,10-tetrahydro-1-methyl 4H-pyrido [4 ',3 ':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine R = (4,5,6-trimethoxy)phenyl-6-(2-chlorophenyl) - 9-(4-tert.butyl)phenylsuphonyl - 7,8, 9,10-tetrahydro-1-methyl 4H-pyrido [4 ',3 ':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine R = (4-tert.butyl)phenyl-6-(2-chlorophenyl) - 9-(3,4-dimethoxy)phenylsulphonyl - 7, 8,9,10-tetrahydro-1-methyl 4H-pyrido [4 ',3 ':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4 diazepine R = (3,4-dimethoxy)phenyl-6-(2-chlorophenyl) - 9-(2,4,6-trimethyl)phenylsulphanyl -7,8,9,10-tetrahydro-1-methyl 4H-pyrido [4 ',3 ':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine R = (2,4,6-trimethyl)phenyl-6-(2-chlorophenyl) - g-(4-methoxy)phenylsulphonyl - 7,8,g, 10-tetrahydro-1-methyl 4H-pyrido [4',3':4,5] thieno [3,2-f]
1,2,4-triazolo [4,3-a] 1,4-diazepine l0 R = (4-methoxy)phenyl-6-(2-chlorophenyl)- 9-[4-(4'-nitrophenoxy)]phenylsulphonyl-7,8,9,10-tetrahydro-1-methyl 4H-pyrido [4 ',3 ':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine R = [4-(4'-nitrophenoxy)]-6-(2-chlorophenyl) - 9-a-thienylphenylsulphonyl - 7,8,9, 10-tetrahydro-1-methyl 4Fi-pyrido [4',3':4,5] thieno [3,2-f]
1,2,4-triazolo [4,3-a] 1,4-diazepine R = a-thienyl-6-(2-chlorophenyl) - 9-a-furylphenylsulphonyl - 7,8,9,10-tetrahydro-1-methyl 4H-pyrido [4 ',3 ':4,5] thieno [3,2-f]
1,2,4-triazolo [4,3-a] 1,4-diazepine R = a-furyl-2~~_ ~ ~~ c~
_ 14 -6-(2-chlorophenyl) - 9-(a-pyrrolyl)sulphonyl - 7,8,9,10_ tetrahydro-1-methyl-4H-pyrido [4°,3°:4,5] thieno [3,2-f]
1,2,4-triazolo [4,3-a] 1,4-diazepine R = a-pyrrolyl-6-(2-chlorophenyl) - 9-(8-quinolyl)sulfonyl - 7,8,9,10-tetrahydro-1-methyl-4H-pyrido-[4°,3°:4,5] thieno [3,2-f]
1,2,4-triazolo [4,3-a] 1,4-diazepine R = (8-quinolyl)-6-(2-chlorophenyl) - 9-(2-naphtyl)sulphonyl - 7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4°,3~:4,5] thieno [3,2-f]
1,2,4-triazolo [4,3-a] 1,4-diazepine R = (2-naphtyl)-6-(2-chlorophenyl) - 9-(4-carboxy)phenylsulphonyl - 7,8,x, 10-tetrahydro-1-methyl-4H-pyrido [4~,3':4,5] thieno [3,2-f]
1,2,4-triazolo [4,3-a] 1,4-diazepine 2o R m (4-carboxy)phenyl-6-(2-chlorophenyl) - 9-[4-(4°-(carboxy)phenyloxy) phenyl]
sulphonyl - 7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4°,3':
4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine R = 4-(4°-carboxy)phenyloxy)phenyl-2~~.3ar~.~

EXAMPLE.18 6-(2-chlorophenyl) - 9-[5-methylthio 2,4-dimethoxy]phenyl sulphonyl - 7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4~,3~:
4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine R = (5-(methylthio) 2,4-(dimethoxy)phenyl-6-(2-chlorophenyl) - 9-[5-mesyl 2,4-dimetho xy] phenyl-sulphonyl - 7,8,9,10-tetrahydro-1-methyl-4H-pyrido [4~,3~:
4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine R ~ (5-mesyl 2,4-dimethoxy)phenyl-6-(2-chlorophenyl) - 9-isopropylsulfonyl - 7,8,9,10-tetra-hydro-1-methyl-4H-pyrido [4',3':4,5] thieno [3,2-f] 1,2,4-triazolo [4,3-a] 1,4-diazepine R ~ isopropyl-TOXICITY
w None of these compounds of this invention was toxic per 0s at dose of l g/kg on mice.
None of the compounds was toxic IP at the dose of 1 g/kg on mice with the exception of the examples 1, 5 and 10 for which the LD 50 was comprised between 0.5 and 1 g/kg.
Taking into account the fact that these compounds are active at doses of about 10-7 M, these toxicity values are deprived of any drawback.

2~D~.~~~.9 PHARMACOLOGY
Various pharmacological determinations have been made on these compounds ; they are summarized as follows :
1) Inhibition of platelet aareaation induced by PAF
This experimentation was conducted according to the method of R. KINLOUGH. RATHBONE, J.P. CAZENAVE, M. PACKHAM and F. MUSTARD, Lab. Invest. 48, 98, 1980. In this test, New Zealand rabbits were used (male New Zealand rabbits of an average weight of 5 kg).
to The determinations are made on a chrono-log Coultronics agregometer, at 57~C coupled with a graphic recorder ; the results of these determinations (in molecular concentration) are reported on the table I on the central column.
2) Inhibition of the binding to benzodiazeoine rece tors The interest of the previous experimentation depends on the results obtained in this experimentation : as a compound of the invention has a benzodiazepine like structure, it is important to check whether the specific benzodiazepine 2o activity would not appear at the dose where platelet agregation was inhibited.
Therefore, this experimentation has been conducted according to the method of MOHLER H. and RICHARD J.G.
Agonist and antagonist benzodiazepine receptor intereaction in vitro, Nature, vol. 294, 763-765, 1981.
This experimentation was conducted on rat brains incubated 1 h 30 at 4'C using 'H-RO-15-1788 and 'H-RO-5-4864 (NEN) as tracers and RO-15-4788 and RO-5-4864 as reference antagonists.

~C~~_~~~.~

The results in molecular concentration are reported in the table I, on the right hand column.

3) Global ischemia on gerbilles For this test, males gerbilles were anaesthetized with brietal at the doses of 35 mg/kg IP; thereafter, both carotides were clamped for 10 minutes, then the clamping was released. Treated animals received each 10 mg/kg of the compounds of one of the examples.
One week later, the animals were killed and both hippocampes were taken, weighed and frozen at -eo°C.
l0 After crushing with 1 ml of TRIS-HCl buffer pH 7.4 for 30 secondes, aliquots of each 50 u1 of this preparation were incubed in each 1 ml of TRIS-HC1 buffer containing 3H-PK 11195 at 2 nM (90 Ci/mmole, NENE, Germany) for 1 hour at 25°C. For each preparation, 3 determinations were made. The density of omega 3 sites (marked by the specific 3H PK 11195 marker) are expressed in f-moles of PK 11195/mg of fresh tissues and converted in percentage of protection compared to control.
The results of this experimentation are reported on the following table II.
PRESENTATION - POSOLOGY
In human therapy, the compounds of the invention may be administered by oral route. Preferred forms of administration include tablets, gelatine capsules and the like. Usual posology is from 50 mg to 500 mg per diem according to the case. Unit dose may contain from 10 to 100 mg, but preferred unit dose is 50 mg, associated with appropriate carriers and agents. when used by injection route, unit doses are from 1 to 20 mg but preferred dose is 5 mg.

1$ _ 2Q~.;.~ i~
TABLE I A
EXAMPLES IC50 BDZ receptors 1 9.63 10 8 4.22 10 6 2 2.25 10 7 I.OS 10 6 3 3.71 10 8 6.33 10 7 4 9.82 10 8 4.56 10 6 1.87 10 7 2.28 106 1.17 10-7 8.72 10'5 7 1.19 10 7 3.33 10 6 8 2.51 1 A 8 7.48 10-6 9 1.22 l0 7 9.30 10 6 1.41 10 9 8.75 10 6 11 1.44 10 7 4.27 10-5 12 1.10 10 7 4.44 10 6 SABLE I B
..
EXAMPLES IC50 BDZ receptors 13 2.1 10 7 1.11 10-6 S

14 6.5 10 8 8.65 10 s 15 4.31 IO ~ 2.15 10 6 16 2.01 10 8 3.05 10 7 17 4.72 10 7 8.25 10 6 18 2.22 10 8 7.63 10'7 19 3.75 10 7 5.64 10 S

20 5.17 10 7 4.28 10 5 2~D~1.~~~ .'~

TABLE II
EXAMPLES Global protection in 1 52.1 ***

2 38.3 **

33.3 **

4 38.7 **

zs.l *

13.8 NS

7 26.6 8 30.5 **

9.4 NS

19.3 11 32.7 **

12 21.4 13 29.3 **

14 17.4 NS

34.8 **

16 23.9 17 7.8 NS

18 10.0 NS

19 8.4 NS

47.5 ***

Claims

1. Thieno-triazolo-diazepine derivative of the formula wherein R represents:
- a straight or branched chain alkyl group having from 1 to 20 carbon atoms;
- a phenyl group, unsubstituted or substituted by a halogen atom, a straight chain or branched chain alkyl group having from 1 to 8 carbon atoms, an alkoxy group having from 1 to 5 carbon atoms, a carboxy group, a mesyl group, a methylthio group, a trifluoromethyl group or a phenoxy group unsubstituted or substituted by a nitro group or a carboxy group; or - a furyl, thienyl, pyrrolyl, quinolyl, naphthyl group;
or a therapeutically acceptable salt thereof.

2. Preparation process of a derivative of claim 1 consisting in reacting the thieno-triazolo-diazepine compound of the formula with RSO2-Cl, in the presence of a mild basic agent, in a polar solvent, at a temperature between about 10° and 30° Celcius, wherein R is defined as in claim 1.

3. A therapeutic composition of matter comprising a therapeutically sufficient amount of one or more derivatives according to claim 1 associated with carriers suitable for the selected administration form.

4. The therapeutic composition according to claim 3, for oral administration, containing from 10 to 100 mg of active ingredient per dose unit.

5. The therapeutic composition according to claim 3, for injections, containing from 1 to 20 mg of active ingredient per dose unit.